Coronary Plaque Burden, as Determined by CardiacComputed Tomography, in Patients with MyocardialInfarction and Angiographically Normal CoronaryArteries Compared to Healthy Volunteers: A ProspectiveMulticenter Observational StudyElin B. Brolin1*, Tomas Jernberg2, Torkel B. Brismar1, Maria Daniel3, Loghman Henareh2,

Jonaz Ripsweden1, Per Tornvall4, Kerstin Cederlund1

1Department of Radiology, Karolinska University Hospital Huddinge and Department of Clinical Science, Intervention and Technology, Division of Medical Imaging and

Technology at Karolinska Institutet, Stockholm, Sweden, 2Department of Medicine, Section of Cardiology, Karolinska University Hospital Huddinge and Karolinska

Institutet, Stockholm, Sweden, 3Cardiology Unit, Department of Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden, 4 Institution

for Clinical Science and Education at Sodersjukhuset, Karolinska Institutet, Stockholm, Sweden

Abstract

Objectives: Patients presenting with acute myocardial infarction and angiographically normal coronary arteries (MINCA)represent a diagnostic and a therapeutic challenge. Cardiac computed tomography (CT) allows detection of coronary arterydisease (CAD) even in the absence of significant stenosis. We aimed to investigate whether patients suffering from MINCAhad a greater coronary plaque burden, as determined by cardiac CT, than a matched group of healthy volunteers.

Methods: Consecutive patients, aged 45 to 70, with MINCA were enrolled in the Stockholm metropolitan area. Patients withmyocarditis were excluded using cardiovascular magnetic resonance imaging. Remaining patients underwent cardiac CT, asdid a reference group of healthy volunteers matched by age and gender, with no known cardiovascular disease. Plaqueburden was evaluated semi-quantitatively on a per patient and a per segment level.

Results: Despite a higher prevalence of smoking and hypertension, patients with MINCA did not have more CAD thanhealthy volunteers. Among 57 MINCA patients and 58 volunteers no signs of CAD were found in 24 (42%) and 25 (43%)respectively. On a per segment level, MINCA patients had less segments with stenosis$20% (2% vs. 5%, p,0.01), as well as asmaller proportion of large (2% vs. 4%, p,0.05) and mixed type plaques (1% vs. 4%, p,0.01). The median coronary calciumscore did not differ between MINCA patients and healthy volunteers (6 vs. 8, ns).

Conclusions: MINCA patients with no or minimal angiographic stenosis do not have more coronary atherosclerosis thanhealthy volunteers, and a large proportion of these patients do not have any signs of CAD, as determined by cardiac CT. TheMINCA patient group is probably heterogeneous, with a variety of different underlying mechanisms. Non-obstructive CAD ismost likely not the most prevalent cause of myocardial infarction in this patient group.

Citation: Brolin EB, Jernberg T, Brismar TB, Daniel M, Henareh L, et al. (2014) Coronary Plaque Burden, as Determined by Cardiac Computed Tomography, inPatients with Myocardial Infarction and Angiographically Normal Coronary Arteries Compared to Healthy Volunteers: A Prospective Multicenter ObservationalStudy. PLoS ONE 9(6): e99783. doi:10.1371/journal.pone.0099783

Editor: Rozemarijn Vliegenthart, University of Groningen, Netherlands

Received January 22, 2014; Accepted May 19, 2014; Published June 17, 2014

Copyright: � 2014 Brolin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the Swedish Heart-Lung Foundation (www.hjart-lungfonden.se) and by the regional agreement on medical training andclinical research (ALF) between Stockholm County Council and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decisionto publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: elin.bacsovics.brolin@ki.se

Introduction

In a considerable number of patients presenting with acute

myocardial infarction who undergo conventional coronary angi-

ography, no significant coronary artery stenoses are found. This

condition is called MINCA (myocardial infarction and angio-

graphically normal coronary arteries) or MINOCA (myocardial

infarction and non-obstructed coronary arteries). Depending on

the definition, the reported prevalence of MINCA ranges between

3% and 18% of all acute myocardial infarctions. [1–5] In women,

however, the prevalence has been reported to be as high as 33%.

[4,5] A number of underlying mechanisms have been proposed,

including vasospasm, embolism, disturbed endothelial function

and coronary artery disease (CAD) with occult rupture of non-

stenotic plaque. [6–8] In a clinical setting, Takotsubo cardiomy-

opathy can be considered a subtype of MINCA. For this

condition, often provoked by stress, additional underlying mech-

anisms have been suggested, such as exaggerated sympathetic

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stimulation and catecholamine toxicity. [9,10] Although awareness

of MINCA has increased, there is still a lack of data clarifying its

different aetiologies and mechanisms.

The development of diagnostic imaging methods has provided

new means for understanding MINCA and its underlying causes.

The use of cardiovascular magnetic resonance imaging (CMR) for

instance, enables differentiation between myocarditis and myo-

cardial infarction, as well as diagnosis of Takotsubo cardiomyop-

athy. [1,11] Cardiac computed tomography (CT) has evolved

substantially during the last few years, and has now achieved very

good accuracy when it comes to diagnosing stenoses of the

coronary arteries, as compared to coronary angiography. [12]

Cardiac CT has also proven highly sensitive in detecting

atherosclerotic plaques in the proximal segments of the coronary

arteries, when compared to intravascular ultrasound. [13] An

important difference between conventional coronary angiography

and cardiac CT is the fact that the former only shows the lumen of

the artery, whilst the latter permits visualization of the vascular

wall as well as the lumen. Cardiac CT allows detection and

characterization of coronary atherosclerotic plaques even when

they do not give rise to stenoses and whether they are calcified or

not. Accordingly, cardiac CT makes it possible to assess

atherosclerotic plaques undetected by conventional coronary

angiography.

Previous studies, using intravascular ultrasound or cardiac CT,

have suggested that CAD is an important underlying cause of

MINCA. [7,14–16] However, none of these studies included a

control group. Since other cardiac CT studies including asymto-

matic subjects have demonstrated a non negligible prevalence of

CAD, the question remains whether the CAD shown in MINCA

patients was necessarily the cause of the myocardial infarction.

[17–19].

The present study is a substudy of the SMINC (Stockholm

Myocardial Infarction with Normal Coronaries) study and aims to

examine whether patients suffering from MINCA have more

coronary atherosclerosis, as assessed by cardiac CT, than a

reference group of healthy volunteers [22].

Materials and Methods

Ethics StatementThe study conforms to the principles of the Declaration of

Helsinki and was approved by the Regional Ethical Review Board

in Stockholm (www.epn.se) and by the Radiation Protection

Committee of the Karolinska University Hospital. Written

informed consent was obtained from all patients and healthy

volunteers.

Study GroupBetween June 2007 and May 2011, patients with MINCA were

screened for the SMINC study at five different coronary care units

in the Stockholm metropolitan area, as described by Collste et al.

[22] Patients were eligible to take part in the study if they were

between 35 and 70 years of age, fulfilled the criteria for acute

myocardial infarction according to the universal definition of

myocardial infarction, [20] and underwent a coronary angiogra-

phy showing no or minimal signs of atherosclerosis (defined as the

presence of plaque discernible on coronary angiography, but no

stenosis exceeding 30% by visual estimation). Coronary angiog-

raphy was performed at the time of initial hospital admission,

according to clinical routines, and evaluated using the modified

American Heart Association 17 segment classification. [21]

Exclusion criteria were a patient history of structural or coronary

heart disease, chronic obstructive lung disease, renal disease, the

use of a pacemaker and an electrocardiogram (ECG) on admission

showing non sinus rhythm or a clinical diagnosis of pulmonary

embolism. CMR was performed on all patients in order to exclude

those with myocarditis. [22] After patient inclusion, the coronary

angiogram as well as the clinical diagnosis of acute myocardial

infarction were re-evaluated by an additional investigator. A

reference group of healthy volunteers, matched by age and gender,

with no known cardiovascular disease, was recruited using a

registry comprising all Stockholm residents. Persons of the same

age and gender as MINCA patients were contacted by mail. If

they were willing to participate and had no history of cardiovas-

cular disease they underwent an exercise stress test, and if the test

was normal they were invited to take part in the study.

Out of 152 patients screened for the SMINC study, 100

MINCA patients were after exclusions described above considered

for the present cardiac CT substudy, as well as 100 healthy

volunteers. Accordingly, the MINCA patients of the present study

form a subgroup of the patients studied by Collste et al. [22]

Additional exclusion criteria for the CT study were age under 45

(due to considerations of radiation dose; 5 MINCA patients and 5

control persons), previous adverse reaction to iodinated contrast

media (1 MINCA patient) and an irregular heart rate (jeopardizing

the diagnostic quality of the CT scan; 1 control person). Out of

100 MINCA patients and 100 healthy volunteers, 61 and 58

respectively agreed to take part in the present study. The CT

examinations of the MINCA patients were performed between 3

and 6 months after the acute event.

Cardiac CT Data AcquisitionExaminations were performed on a 64-slice CT scanner

(LightSpeed VCT XT; GE Healthcare, Milwaukee, WI, USA).

A prospectively ECG-triggered scan protocol was used: detector

configuration 6460.625 mm, rotation time 350 ms, tube potential

120 kV, tube current 450–650 mA (according to patient size). The

scans were performed in diastole, in general at 70–75% of the RR

interval, with a padding of 100–200 ms, depending on heart rate

and variability. The contrast agent used was iodixanol 320 mg I/

ml (Visipaque, GE Healthcare, Stockholm, Sweden), which was

administered using a dual-head injector (Medrad, Stellant Dual

Head Injector, Pittsburgh, PA, USA) and a triple-phase protocol.

The contrast agent was individually dosed, based on body weight

(400 mg I/kg, 75–100 ml iodixanol), with a fixed injection time

(15 s), resulting in an injection rate of 5–7 ml/s. This was followed

by a 50 ml mixture of 40% iodixanol and 60% saline and finally

by a 50 ml saline chaser. In the absence of contraindications and

depending on the initial heart rate, patients received metoprolol

(25–100 mg) per os prior to the examination. Patients also

received sublingual nitroglycerine (0.4 mg) 4 minutes before the

scan.

To assess the coronary calcium score, a non-enhanced scan was

performed, using a prospectively ECG-triggered scan protocol:

tube potential 120 kV, tube current 200 mA.

Cardiac CT Data AnalysisThe Cardiac CT exam was analysed independently by three

readers (two experienced readers with level 2 and one reader with

level 1 according to ACCF/AHA levels of competence), [23] who

were blinded to all clinical information. A subsequent joint reading

was performed and a consensus reached.

Cardiac CT data analysis was performed using the CardIQ

Xpress software on the Advantage Workstation 4.4 (GE

Healthcare, Milwaukee, WI, USA). Axial source images, multi-

planar and curved multiplanar reformats as well as thin-slab

maximum intensity projections were used. The optimal image

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display setting for lumen and plaque assessment was chosen on an

individual basis, but in general at a window width of 800–

1000 HU and a level of 100–200 HU. Coronary arteries were

subdivided into 17 segments, according to the modified American

Heart Association classification. [21] Initially, each segment was

assessed regarding image quality and evaluability. Segments were

considered non-evaluable if artifacts prevented reliable assessment

of the lumen or the vessel wall (e. g. due to motion, image noise or

heavy calcification). Secondly, each segment was visually evaluated

with regard to the presence of stenosis (A), plaque size (B) and

composition (C). A plaque was defined as any structure, discernible

in at least two planes, within or adjacent to the vessel lumen, which

could be clearly separated from the vessel lumen and from

adjacent soft tissue.

A. Lesions were quantified for stenosis by visual estimation,

comparing the minimal lumen of the stenotic area with the

lumen of the adjacent proximal unaffected segment, and

expressed in terms of diameter stenosis:,20%, 20–50% or$

50%.

B. The size of the atherosclerotic plaque was determined by

measuring the length of the plaque on longitudinal sections

and arbitrarily classified as: small (,4 mm), medium (4–

8 mm) or large ($8 mm).

C. Plaque composition was visually assessed based on the

presence or absence of calcified elements: non-calcified

coronary artery plaque, mixed coronary artery plaque or

calcified coronary artery plaque, the latter with $50%

calcified tissue. [24].

In the case of more than one atherosclerotic plaque in a single

segment, only the greatest degree of stenosis, the largest plaque

size and the most pronounced calcification was considered.

Coronary Calcium ScoreThe coronary calcium score was calculated using semi-

automatic software (SmartScore 4.0, GE Healthcare, Milwaukee,

WI, USA) on the Advantage Workstation 4.4 (GE Healthcare,

Milwaukee, WI, USA). The total calcium burden of the coronary

arteries was reported in terms of AJ-130 score, based on the

scoring algorithm of Agatston et al. [25].

Statistical AnalysisIn order to evaluate hypotheses of variables in contingency

tables, the chi-square test was used or, in the case of small expected

frequencies, Fisher’s exact two-sided test. Statistical comparisons

for testing differences between two independent groups were made

using the Student’s t-test for uncorrelated means, after validation

of normal distribution by use of the Shapiro Wilk test. In the case

of non-normal distribution the Mann-Whitney test was used. In

addition, descriptive statistics was used to characterize the data. All

analyses were carried out using the SAS system and the 5% levels

of significance were considered. In the case of a statistically

significant result the probability value (p-value) has been given.

Due to the nature of the study, an initial exploratory study, the

sample size was not determined based on power or clinical

difference. The number of patients participating in the study was

chosen for practical reasons, not statistical. However, in order to

estimate statistical power, one could consider the per segment

analysis (n = 765+781) and a binomial endpoint (segment with or

without CAD) and a 5% level of significance. Anticipating a

prevalence of CAD of 10% in the control group and 15% in the

MINCA group would yield a power of 85%.

Results

Of the 119 (61 MINCA+58 volunteers) cardiac CT exams

performed, 4 exams of MINCA patients had to be excluded, 3 due

to motion artifacts resulting in,7 evaluable segments and 1 due to

the heart not being completely covered by the scan. Thus, cardiac

CT exams of 57 MINCA patients and 58 healthy volunteers were

further analyzed. From these exams 15 (1.9%) individual segments

in the MINCA group and 11 (1.4%) in the reference group were

non-evaluable and excluded from analyses. Figure 1 shows an

example of a coronary artery in a MINCA patient, as visualized by

cardiac CT and by conventional coronary angiography. Figure 2

shows examples of different plaque types as seen by cardiac CT.

Baseline characteristics of patients with MINCA and healthy

volunteers are compared in Table 1. Current smoking and treated

hypertension were more common in the MINCA group.

Regarding all other variables the two groups were comparable.

Out of 57 MINCA patients, 56 presented with no signs of heart

failure (Killip class 1) and only one with heart failure, consistent

with Killip class 2. Signs of acute ischemia (ST-T changes or left

bundle branch block) on admission ECG were present in 31 (54%)

MINCA patients, of whom 10 had ST elevations. The median

(IQR) maximum troponin level was 18 (7–43) times greater than

the upper limit of normal. Myocardial infarction was detectable

with CMR in 11 (19%) patients. The criteria for Takotsubo

cardiomyopathy was fulfilled in 15 (26%).

The cardiac CT plaque burden analyses are presented in

Tables 2 and 3, on per patient (Table 2) and per segment (Table 3)

basis, comparing the MINCA group with the reference group. On

a per patient level there were no statistically significant differences in

severity or extent of CAD. Twentyfour (42%) MINCA patients

and 25 (43%) healthy subjects had no signs of CAD. When

analyzing the data on a per segment level, however, there were

statistically significant differences regarding degree of stenosis,

plaque size and plaque composition. MINCA patients had less

segments with stenosis $20% compared to healthy volunteers (2%

vs 5%, p,0.01) They also exhibited a smaller proportion of large

plaques (2% vs 4%, p,0.05) and mixed type coronary artery

plaques (1% vs 4%, p,0.01). The calcium scores within each

group were diverse, but no significant differences were found

between the groups. No differences were found regarding CT

plaque burden when MINCA patients with and without MI

detected by CMR were compared or when MINCA patients with

and without ST elevations were compared (Table S1). Nor were

there any differences in plaque burden between MINCA patients

with and without a diagnosis of Takotsubo cardiomyopathy (Table

S1). No statistically significant difference was demonstrated

regarding peak troponin levels between MINCA patients with

and without CAD. There were no differences in terms of baseline

characteristics when MINCA patients without CAD were com-

pared to those with CAD demonstrated by cardiac CT (Table S2).

Discussion

This study is the first to analyze coronary plaque burden in

patients with MINCA by means of cardiac CT, with a matched

reference group for comparison. The most important finding was

the fact that patients with MINCA did not have more coronary

atherosclerosis than healthy volunteers, despite a higher frequency

of smoking and hypertension in the MINCA group. In addition, a

high proportion of MINCA patients (42%) did not exhibit any

signs of CAD, as demonstrated by cardiac CT, which strongly

suggests that there are underlying causes other than CAD in a

significant number of MINCA patients. A finding that further

strengthens this hypothesis was the fact that MINCA patients had

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a lower rate of large size atherosclerotic plaques and mixed type

coronary artery plaques compared to healthy volunteers. Such

plaque characteristics have been shown to imply a more

vulnerable plaque, more prone to rupture [26–28].

In the literature there are several definitions and terms used to

designate myocardial infarction in the absence of significant CAD.

The term MINOCA (myocardial infarction and non-obstructed

coronary arteries) is often used, since many studies have included

patients with ,50% angiographic stenosis. However, the term

MINCA has been chosen for this study, in order to stress the fact

that only patients with no or minimal signs of atherosclerosis on

coronary angiography were included.

The findings of the current study partly contradict findings of a

recent study by Aldrovandi et al., where only 16% of MINCA

patients had no signs of CAD when examined with cardiac CT.

[16] However, this difference can probably be explained by

different inclusion criteria. In the previous study patients with ,

50% angiographic diameter stenosis were included, whereas in the

current study a more rigorous definition was used, including only

patients with no or minimal signs of atherosclerosis. The mean

degree of stenosis, as determined by cardiac CT, was .30% in the

previous study, whereas the median degree of stenosis in the

present study was ,20%. Hence, applying a more rigorous

definition of ‘‘normal coronary angiogram’’ seems useful in order

to identify a patient group that is far less likely to have CAD. In

addition, only patients with evidence of myocardial infarction on

CMR were included in the study by Aldrovandi et al., whereas the

present study also included patients with smaller myocardial

infarctions, proven by biochemical markers but not detectable by

CMR.

A study by Reynolds et al. supports that CAD is a major cause of

myocardial infarction in patients with higher degrees of non-

obstructive stenosis (,50%) at coronary angiography, but not

necessarily in patients with no or minimal signs of atherosclerosis.

[7] In their study women with myocardial infarction without

angiographically obstructive CAD underwent intravascular ultra-

sound, which revealed plaque ruptures and ulcerations in 38% of

patients. A higher degree of stenosis was found in patients with

plaque disruption (median degree of stenosis 40%) compared to

patients without plaque disruption. One third of patients had no

signs of atherosclerosis on coronary angiography and, interesting-

ly, none of these patients had plaque disruption. Consequently, it

seems likely that the frequency of plaque disruption would be

smaller in the present study group, with less severe CAD.

Figure 1. The right coronary artery in a patient presenting with acute myocardial infarction. Cardiac computed tomography (A) shows alarge atherosclerotic plaque and more distally a small plaque, both with ,20% stenosis. Coronary angiography (B) shows only minimal signs ofatherosclerosis.doi:10.1371/journal.pone.0099783.g001

Figure 2. Different plaque types, as seen by cardiac computed tomography. A non-calcified plaque is shown in longitudinal and crosssection (A and B). The degree of stenosis was 20–50%. A large mixed plaque is shown in longitudinal section (C) and in cross section at the level ofnon calcified (D) and calcified (E) components. A large calcified plaque is shown to the right. (F and G). The mixed and calcified plaques (C to G) wereboth eccentric in location and the degree of stenosis was ,20%.doi:10.1371/journal.pone.0099783.g002

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This study cannot explain the underlying cause of MINCA.

One explanation could be that an important proportion of

MINCA cases are in fact Takotsubo cardiomyopathy, which was

found in 26% of the study group. For the MINCA patients who

had CAD, this may at least for some patients have been the cause

of the myocardial infarction. Plaque disruption with transient

thrombus formation might be one plausible mechanism and

vasospasm another. [7] There was a higher frequency of smoking

in the MINCA group, which may in turn increase the risk of

thrombosis, as well as vasoconstriction. An increased resistance to

activated protein C has been reported in MINCA patients, which

supports the theory that thrombosis is involved in the aetiology of

MINCA [4].

The present study has limitations. Although being the largest

study of its kind, the sample size was limited. Thus, lack of

significant differences may still be caused by lack of power to

detect such differences. However, the data show a tendency

towards more severe CAD in the reference group compared to the

MINCA-group, rather than the other way round.

The fact that MINCA patients, on a per segment level, showed

a lower frequency of stenoses $20% than healthy subjects can

probably be explained by the selection process, where MINCA

patients per definition had no or minimal stenosis as determined

Table 1. Baseline characteristics.

MINCA, n=57 Healthy subjects, n = 58

Age (years) 6065 6166

Female 42 (74%) 39 (67%)

Present smoking 10 (18%) 2 (3%)*

Prior smoking 17 (30%) 23 (40%)

Family history of CAD 16 (28%) 14 (24%)

Diabetes mellitus 1 (2%) 0 (0%)

Treated hypertension 19 (33%) 6 (10%){

Treated hyperlipidemia 8 (14%) 3 (5%)

BMI (kg/m2) 25.863 25.863

Abbreviations: MINCA, myocardial infarction with angiographically normal coronary arteries; CAD, coronary artery disease; BMI, body mass index; SD, standard deviation.Data are presented as mean 6 SD or absolute value (percentage).*P,0.05,{P,0.01, using Fisher’s exact test.doi:10.1371/journal.pone.0099783.t001

Table 2. Cardiac CT plaque burden per patient.

MINCA patients,n = 57

Healthy volunteers,n= 58 P

Severity of CAD* No CAD 24 (42%) 25 (43%) ns

Stenosis ,20% 22 (39%) 23 (40%)

Stenosis 20–50% 11 (19%) 9 (16%)

Stenosis $50% 0 (0%) 1 (2%)

All CAD{ 0 segments 24 (42%) 25 (43%) ns

1 segments 14 (25%) 10 (17%)

2 segments 8 (14%) 12 (21%)

3 segments 4 (7%) 6 (10%)

4 segments 2 (4%) 0 (0%)

5 segments 3 (5%) 1 (2%)

6 segments 0 (0%) 0 (0%)

7 segments 0 (0%) 0 (0%)

8 segments 2 (4%) 1 (2%)

9 segments 0 (0%) 1 (2%)

10 segments 0 (0%) 2 (3%)

Calcium score (AJ-130) 6 (0–778) 8 (0–1882) ns

Abbreviations: Cardiac CT, cardiac computed tomography; MINCA, myocardial infarction with angiographically normal coronary arteries; CAD, coronary artery disease;ns, non significant. Values are presented as absolute value (percentage) or median (range).*refers to the maximum diameter stenosis;{refers to obstructive and non-obstructive CAD.doi:10.1371/journal.pone.0099783.t002

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by conventional coronary angiography. One could argue that the

reference group should have been selected by excluding individ-

uals with angiographic coronary stenoses. This was however not

achievable, since it is not ethically possible to perform invasive

coronary angiography on healthy volunteers. Still, on a per patient

level there were roughly equal numbers of MINCA patients (19%)

and healthy controls (18%) with stenosis $20%. Only 57 of the

initial 100 MINCA patients were included in the cardiac CT

analyses. There were however no differences in baseline charac-

teristics when these patients were compared with the 43 MINCA

patients who did not participate in the cardiac CT study (Table

S3). The study population mainly reflects a northern European

ethnic group, the majority being women, which might affect

generalizability. However, the female predominance is not

surprising, since it reflects the higher prevalence of MINCA in

women compared to men. Although 64 detector cardiac CT has

proven highly sensitive in detecting atherosclerotic plaques, its

spatial resolution is limited, which makes it hazardous to assess

very small structures. A study comparing cardiac CT plaque

detection and quantification with IVUS measures showed a very

good diagnostic accuracy for cardiac CT to detect atherosclerotic

plaques on a segmental level. However, the sensitivity decreased

for smaller plaques and for plaques located more distally in the

coronary arteries. [29] Hence, early coronary atherosclerosis, with

very subtle changes of the vessel wall, as well as distal lesions might

remain undetected by cardiac CT. For the MINCA patients there

was a time span of 3 to 6 months between the acute event and the

CT examination, which might have had minor influence on the

results. A semi-quantitative method was used to estimate plaque

burden. It could be debated whether an automated, non-user

dependent method should have been used. However, such

automated approaches have not been thoroughly validated, whilst

semi-quantitative methods relying on visual assessment for plaque

detection and characterization have been described in several

studies and have been found to entail good intra- and interob-

server variability [30].

The current findings together with findings of previous studies

suggest that patients with MINCA compose a heterogeneous

group, with a variety of underlying causes of the myocardial

infarction. It seems that in patients with moderate angiographic

coronary stenosis, CAD with plaque disruption might be an

important cause of the myocardial infarction, whilst in patients

with no or minimal angiographic stenosis the myocardial

infarction is more likely to have other causes than established

CAD. It is now well recognized that atherosclerosis is a

heterogeneous process, including for instance inflammation and

endothelial dysfunction, and additional research is warranted in

order to investigate the role of these processes in the MINCA

patient group.

Since the prognosis for patients suffering from MINCA is not

benign, [31,32] it is of great importance to further clarify the

underlying mechanisms, in order to offer patients appropriate

treatment and care.

Supporting Information

Table S1 Cardiac CT plaque burden, comparing subgroups of

MINCA patients.

(PDF)

Table S2 Baseline characteristics for MINCA patients with and

without CAD.

(PDF)

Table S3 Baseline characteristics for MINCA patients that

participated and did not participate in the CT substudy.

(PDF)

Author Contributions

Conceived and designed the experiments: EBB TJ TBB MD LH JR PT

KC. Performed the experiments: EBB JR KC. Analyzed the data: EBB TJ

TBB PT KC. Contributed reagents/materials/analysis tools: EBB MD LH

JR PT KC. Wrote the paper: EBB TJ TBB PT KC.

Table 3. Cardiac CT plaque burden per segment.

MINCA patients,765 segments

Healthy volunteers,781 segments P

Severity of CAD No CAD 684 (89%) 687 (88%) ,0.01*

Stenosis ,20% 68 (9%) 58 (7%)

Stenosis 20–50% 13 (2%) 35 (4%)

Stenosis $50% 0 (0%) 1 (0.1%)

Plaque size No CAD 684 (89%) 687 (88%) 0.04*

Small 41 (5%) 31 (4%)

Medium 24 (3%) 29 (4%)

Large 16 (2%) 34 (4%)

Plaque composition No CAD 684 (89%) 687 (88%) 0.04*

Non-calcified plaque 10 (1%) 10 (1%)

Mixed plaque 10 (1%) 28 (4%)

Calcified plaque 61 (8%) 56 (7%)

Abbreviations: Cardiac CT, cardiac computed tomography; MINCA, myocardial infarction with angiographically normal coronary arteries; CAD, coronary artery disease;Values are presented as absolute value (percentage).*P-values apply to the comparison of the four categories in the two columns to the left of the value, using the chi-square test.doi:10.1371/journal.pone.0099783.t003

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Cardiac CT in MINCA Patients and Healthy Volunteers

PLOS ONE | www.plosone.org 7 June 2014 | Volume 9 | Issue 6 | e99783